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PubMed2026

POU2F3 expression in lung squamous cell carcinoma: transcriptomic and immunohistochemical profiling with prognosis.

BACKGROUND: Lung squamous cell carcinoma (LUSC) lacks well-defined molecular targets. This study investigated the clinical and biological relevance of POU class 2 homeobox 3 (POU2F3), a tuft cell-associated transcription factor, in LUSC. METHODS: RNA sequencing data of patients with LUSC from The Cancer Genome Atlas (TCGA cohort, n = 190) was analysed and compared to a cohort of surgically resected cases analyzed via immunohistochemistry (IHC cohort, n = 137). Prognostic impact was assessed via survival analyses. Transcriptomic features, pathway enrichment, and immune profiles were evaluated via differentially expressed gene analysis, Gene Set Enrichment Analysis, and CIBERSORTx. RESULTS: High POU2F3 expression independently predicted poor overall survival in the TCGA cohort (HR = 2.06, 95% CI: 1.04-4.08, P = 0.039). In contrast, POU2F3 expression was not prognostic in the IHC cohort (P = 0.995). Morphologically, POU2F3-positive tumours were enriched for non-keratinizing and poorly differentiated subtypes. Transcriptomic analysis showed suppression of proliferation and immune-related pathways (FDR < 0.001), with suggestive enrichment of the TGF-β (FDR = 0.143) and p53 (FDR = 0.229) signaling pathways. On immune deconvolution, POU2F3-high tumours showed a nominal increase in activated dendritic cells, which did not withstand multiple testing correction. POU2F3 protein was detected in 12.4% of tumours and was significantly associated with p53 or RB1 abnormalities (single or double) (P = 0.028). CONCLUSIONS: POU2F3 marks a transcriptionally distinct, early-stage subtype of LUSC with keratinization-related features. Its prognostic relevance appears context-dependent and requires prospective validation in uniformly treated cohorts.

Humans↗

PubMed2002

In silico toxicology: simulating interaction thresholds for human exposure to mixtures of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane.

In this study, we integrated our understanding of biochemistry, physiology, and metabolism of three commonly used organic solvents with computer simulation to present a new approach that we call "in silico" toxicology. Thus, we developed an interactive physiologically based pharmacokinetic (PBPK) model to predict the individual kinetics of trichloroethylene (TCE), perchloroethylene (PERC), and methylchloroform (MC) in humans exposed to differently constituted chemical mixtures of the three solvents. Model structure and parameterization originate from the literature. We calibrated the single-compound PBPK models using published data and described metabolic interactions within the chemical mixture using kinetic constants estimated in rats. The mixture model was used to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels and total amount of TCE metabolites generated, in rats and humans. Assuming that a 10% change in the biomarkers corresponds to a significant health effect, we calculated interaction thresholds for binary and ternary mixtures of TCE, PERC, and MC. Increases in the TCE blood levels led to higher availability of the parent compound for glutathione conjugation, a metabolic pathway associated with kidney toxicity/carcinogenicity. The simulated change in production rates of toxic conjugative metabolites exceeded 17% for a corresponding 10% increase in TCE blood concentration, indicating a nonlinear risk increase due to combined exposures to TCE. Evaluation of metabolic interactions and their thresholds illustrates a unique application of PBPK modeling in risk assessment of occupational exposures to chemical mixtures.

Biological Availability↗

PubMed2026

Histopathological evaluation of RPL5 expression in triple-negative breast cancer: an integrated immunohistochemical and transcriptomic study.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high invasiveness, limited therapeutic options, and unfavorable clinical outcomes. Ribosomal protein L5 (RPL5), a component of the large ribosomal subunit, has been implicated in ribosome biogenesis, translational regulation, and p53-associated cellular processes. This study investigated the immunohistochemical expression pattern of RPL5 in TNBC tissues and explored its potential biological significance through integrated transcriptomic analyses. Tumor tissues from 37 patients with TNBC and 7 adjacent non-tumorous breast tissues were collected from the Affiliated Tumor Hospital of Xinjiang Medical University between December 2017 and December 2023. RPL5 protein expression was evaluated by immunohistochemistry, and its association with clinicopathological characteristics was analyzed. Public transcriptomic datasets from TCGA-BRCA and GEO were further used to validate RPL5 expression patterns in TNBC. Co-expression analysis and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate potential biological functions and signaling pathways associated with RPL5. Immunohistochemical analysis demonstrated significantly lower RPL5 protein expression in TNBC tissues compared with adjacent normal breast tissues (p=0.001). In contrast, transcriptomic analyses revealed significantly higher RPL5 expression in TNBC compared with non-TNBC breast cancer subtypes (p<0.001). No significant associations were observed between RPL5 expression and clinicopathological parameters, including age, tumor size, menopausal status, TNM stage, histological grade, or lymph node metastasis (all p>0.05). Survival analysis showed no significant difference in overall survival between patients with high and low RPL5 expression. Functional enrichment analyses indicated that RPL5-related genes were predominantly involved in ribosome biogenesis, translational regulation, and p53-related signaling pathways. These findings suggest that abnormal RPL5 expression may be associated with TNBC biology through ribosome-related programs, although causal roles require functional validation. RPL5 may represent a potential histopathological and molecular indicator associated with TNBC biology, although its precise functional role requires further experimental validation.

Humans↗

PubMed2004

Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study.

OBJECTIVE: The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated. METHODS: In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography. RESULTS: FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet. CONCLUSION: This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.

Adolescent↗

PubMed2004

Multidisciplinary approach to breast cancer management.

The 21st Annual Miami Breast Cancer Conference took place in Miami Beach, Florida, United States, February 25-28, 2004. This meeting aimed to provide practicing surgical and medical oncologists with a multidisciplinary approach to the practice of breast cancer management with incorporation of molecular biologic translation from laboratory to bedside. The expanding knowledge in molecular biology has given rise to the potential for the use of gene expression profiles, molecular fingerprinting and biomarkers for clinical decision making. The theme of this year's meeting was stated to be, "What can you learn that you can use Monday morning and what can you look forward to on Friday?" It is the focus on the most recent practical advances that attracted more than 450 international participants to this 3-day meeting. More than half of all presentations explored recent advances in early breast cancer biology, predictive and prognostic markers, prevention and early diagnosis. This report will collate various presentations to attempt to present a coherent picture of the advances in this area.

Antineoplastic Agents↗

PubMed2006

[The effects of different clinicopathologic variables on serum protein fingerprint in hepatocellular carcinoma patients].

OBJECTIVE: To investigate the effects of different clinicopathologic variables on serum protein fingerprint in hepatocellular carcinoma (HCC) patients. METHODS: Serum samples were collected from 112 HCC patients, Special serum protein or peptide spectra was determined by surface enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) measurement after treating the sample onto weak cation exchange (WCX2) protein chip for each case. The serum protein profiles were compared by BioMarker Wizard Software among the patients stratified according to gender, AFP, presence of portal vein tumor thrombus (PVTT), tumor size, tumor number, presence of cirrhosis, respectively. RESULTS: According to serum protein fingerprints of 112 HCC patients, a total of 100 protein peaks were identified at the m/z value ranging from 1100 to 30,000. (1) Sixteen significant differential proteins were found between the groups of HCC with single tumor and those with multiple tumors (P < 0.01). (2) Only one significant differential protein was found between the groups of HCC with tumor size > 3 cm and those with tumor size 5 cm and those with tumor size 10 cm and those with tumor size <or= 10 cm (P < 0.01). (3) Sixteen significant differential proteins were found between the groups of macroscopic portal vein tumor thrombus (Ma-PVTT) and those without PVTT (N-PVTT); Only 2 significant differential protein were found between the groups of microscopic portal vein tumor thrombus (Mi-PVTT) and N-PVTT (P < 0.01); eight significant differential proteins were found between the groups of Ma-PVTT and Mi-PVTT (P < 0.01). (4) No significant differential protein was found when patients stratified according to gender, presence of cirrhosis and AFP. CONCLUSIONS: PVTT, tumor number and tumor size had significant effects on serum protein fingerprint, while no significant effect on serum protein from gender, presence of cirrhosis and AFP. The most profound impact on the serum protein was attained when cutoff was chosen to be presence of Ma-PVTT compared to less effect from Mi-PVTT and 5cm for tumor size.

Adult↗

PubMed2026

Integrated pan-cancer profiling highlights OSR2 as a prognostic indicator and immune-associated biomarker.

BACKGROUND: Odd-skipped-related 2 (OSR2), encoded by the OSR2 gene, has been reported to function as a checkpoint associated with CD8⁺ T-cell exhaustion in the tumor microenvironment of solid malignancies, suggesting its potential as a therapeutic target to improve immunotherapeutic responses. Nevertheless, the molecular and clinical significance of OSR2 across diverse cancer types has not yet been systematically investigated, and its pan-cancer expression profile, prognostic implications, and associations with tumor immunity remain to be fully elucidated. METHODS: In this study, we integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) portal, and the Human Protein Atlas to construct a systematic pan-cancer profile of OSR2. The prognostic value of OSR2 was comprehensively assessed using univariate Cox regression, survival analysis, and receiver operating characteristic (ROC) curve analysis. In addition, we performed an in-depth analysis of the relationships between OSR2 and multiple molecular and immunological features, including copy number variation (CNV), DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune-related gene expression, immune cell infiltration, and drug sensitivity, with the aim of exploring its potential immunological associations with the tumor microenvironment. RESULTS: OSR2 expression was significantly upregulated or downregulated in the majority of tumor tissues relative to normal counterparts and exhibited distinct cancer-type-specific patterns across clinical stages. CNV alterations and aberrant DNA methylation were closely associated with abnormal OSR2 mRNA expression in multiple cancers. Prognostic analyses indicated that OSR2 expression was significantly associated with overall survival, disease-specific survival, disease-free interval, and progression-free interval across multiple cancer types, showing either risk-associated or protective associations in a tumor-context-dependent manner. Furthermore, OSR2 expression showed strong associations with immune cell infiltration, particularly T-cell subsets, and was significantly correlated with the expression of multiple immune checkpoint-related genes across diverse malignancies. OSR2 expression was also closely associated with TMB, MSI, and sensitivity to multiple anticancer agents. CONCLUSION: Taken together, these findings suggest that OSR2 is associated with prognosis and immune-related features across multiple cancer types. OSR2 may be linked to features of the tumor immune microenvironment through its relationships with immune cell infiltration, immune checkpoint gene expression, and genomic instability, and thus may serve as a candidate biomarker for further investigation in cancer immunotherapy.

CD8⁺ T-cell↗

PubMed2026

Predictive biomarkers in cancer immunotherapy for genitourinary malignancies.

Immunotherapy has transformed the management of genitourinary cancers, offering durable responses in selected patient groups. However, the clinical benefit of immune checkpoint inhibitors varies significantly across renal cell carcinoma, urothelial carcinoma, and prostate cancer, underscoring the need for reliable predictive biomarkers. This review summarizes current knowledge on established and emerging biomarkers, including PD L1 expression, tumor mutational burden, molecular subtypes, genomic alterations, tumor microenvironment characteristics, circulating biomarkers, microbiome influences, and multi omic integrative approaches. We discuss their potential clinical relevance, limitations, and applicability across different tumor types. Future directions emphasize the development of composite biomarkers, standardization of testing platforms, real time monitoring strategies, and the integration of advanced technologies such as artificial intelligence and spatial profiling. Understanding and validating these biomarkers will be essential for optimizing personalized immunotherapy in genitourinary cancers.

Circulating tumor DNA↗

PubMed2005

Translational studies for target-based drugs.

The biological background for the clinical and prognostic heterogeneity among tumors within the same histological subgroup is due to individual variations in the biology of tumors. The number of investigations looking at the application of novel technologies within the setting of clinical trials is increasing. The most promising way to improve cancer treatment is to build clinical research strategies on intricate biological evidence. New genomic technologies have been developed over recent years. These techniques are able to analyze thousands of genes and their expression profiles simultaneously. The purpose of this approach is to discover new cancer biomarkers, to improve diagnosis, predict clinical outcomes of disease and response to treatment, and to select new targets for novel agents with innovative mechanisms of action. Gene expression profiles are also used to assist in selecting biomarkers of pharmacodynamic effects of drugs in the clinical setting. Biomarker monitoring in surrogate tissues may allow researchers to assess "proof of principle" of new treatments. Clinical studies of biomarkers monitoring toxicity profiles have also been done. Such pharmacodynamic markers usually respond to treatment earlier than clinical response, and as such may be useful predictors of efficacy. Epidermal growth factor receptor (EGFR) mutation in lung cancer tissues is a strong predictive biomarker for EGFR-targeted protein tyrosine kinase inhibitors. Monitoring of EGFR mutation has been broadly performed in retrospective and prospective clinical studies. However, global standardization for the assay system is essential for such molecular correlative studies. A more sensitive assay for EGFR mutation is now under evaluation for small biopsy samples. Microdissection for tumor samples is also useful for the sensitive detection of EGFR mutation. Novel approaches for the detection of EGFR mutation in other clinical samples such as cytology, pleural effusion and circulating tumor cells are ongoing.

Biomarkers, Tumor↗

PubMed2005

Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia.

Microarray techniques hold great promise for identifying risk factors for schizophrenia (SZ) but have not yet generated widely reproducible results due to methodological differences between studies and the high risk of type I inferential errors. Here we established a protocol for conservative analysis and interpretation of gene expression data from the dorsolateral prefrontal cortex of SZ patients using statistical and bioinformatic methods that limit false positives. We also compared brain gene expression profiles with those from peripheral blood cells of a separate sample of SZ patients to identify disease-associated genes that generalize across tissues and populations and further substantiate the use of gene expression profiling of blood for detecting valid SZ biomarkers. Implementing this systematic approach, we: (i) discovered 177 putative SZ risk genes in brain, 28 of which map to linked chromosomal loci; (ii) delineated six biological processes and 12 molecular functions that may be particularly disrupted in the illness; (iii) identified 123 putative SZ biomarkers in blood, 6 of which (BTG1, GSK3A, HLA-DRB1, HNRPA3, SELENBP1, and SFRS1) had corresponding differential expression in brain; (iv) verified the differential expression of the strongest candidate SZ biomarker (SELENBP1) in blood; and (v) demonstrated neuronal and glial expression of SELENBP1 protein in brain. The continued application of this approach in other brain regions and populations should facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for SZ. The identification of valid peripheral biomarkers for SZ may ultimately facilitate early identification, intervention, and prevention efforts as well.

Biomarkers↗

PubMed2005

Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation.

PURPOSE: Patients with localized esophageal carcinoma have a 5-year survival rate of less than 20%. Patients are often treated similarly (ie, with preoperative chemoradiotherapy) but the outcomes vary greatly. Chemoradiotherapy and surgery can result in significant undesirable consequences. Currently, however, there are no tools to help select optimum therapy. We hypothesized that gene expression profiling could provide clues and biomarkers for selection of therapy. METHODS: Pretreatment endoscopic cancer biopsies from 19 patients (16 with adenocarcinoma, two with squamous cell carcinoma, and one with adenosquamous carcinoma) enrolled onto a preoperative chemoradiotherapy protocol were profiled using oligonucleotide microarrays. Surgical specimens following therapy were assessed for the degree of pathologic response. On the basis of array data, selected genes were analyzed by polymerase chain reaction. RESULTS: Unsupervised hierarchical cluster analysis segregated the cancers into two molecular subtypes, each consisting 10 and nine specimens, respectively. Most cancers (five of six) that had pathologic complete response (pathCR) clustered in molecular subtype I. Subtype II, with one exception, consisted cancers that had less than pathCR (< pathCR). Using a combination marker approach, levels of PERP, S100A2, and SPRR3 allowed discrimination of pathCR from < pathCR with high sensitivity and specificity (85%). Pathway analysis identified apoptotic pathway as one of the key functions downregulated in molecular type II in comparison with type I. CONCLUSION: These encouraging, albeit preliminary, data suggest that expression profiling may distinguish cancers with different pathologic outcome. This is the first report to show subtypes of esophageal cancers with distinct molecular signatures. The potential of PERP, S100A2, and SPRR3 as biomarkers of pathCR warrants further validation.

Adenocarcinoma↗

PubMed1999

Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women.

PURPOSE: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction. PATIENTS AND METHODS: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, blood cell count, fibrinogen, antithrombin III, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer. RESULTS: The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mL) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 mg every other day, 51.2 +/- 24.1 and 90.7 +/- 48.0 with 10 mg/d, and 136.0 +/- 52.7 and 230.6 +/- 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations. CONCLUSION: An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent.

Antineoplastic Agents, Hormonal↗

PubMed2003

Metabolic biomarker and kinase drug target discovery in cancer using stable isotope-based dynamic metabolic profiling (SIDMAP).

Tumor cells respond to growth signals by the activation of protein kinases, altered gene expression and significant modifications in substrate flow and re-distribution among biosynthetic pathways. This results in a proliferating phenotype with altered cellular function. These transformed cells exhibit unique anabolic characteristics, which includes increased and preferential utilization of glucose through the non-oxidative steps of the pentose cycle for nucleic acid synthesis but limited de novo fatty acid synthesis and TCA cycle glucose oxidation. This primarily non-oxidative anabolic profile reflects an undifferentiated highly proliferative aneuploid cell phenotype and serves as a reliable metabolic biomarker to determine cell proliferation rate and the level of cell transformation/differentiation in response to drug treatment. Novel drugs effective in particular cancers exert their anti-proliferative effects by inducing significant reversions of a few specific non-oxidative anabolic pathways. Here we present evidence that cell transformation of various mechanisms is sustained by a unique disproportional substrate distribution between the two branches of the pentose cycle for nucleic acid synthesis, glycolysis and the TCA cycle for fatty acid synthesis and glucose oxidation. This can be demonstrated by the broad labeling and unique specificity of [1,2-(13)C(2)]glucose to trace a large number of metabolites in the metabolome. Stable isotope-based dynamic metabolic profiles (SIDMAP) serve the drug discovery process by providing a powerful new tool that integrates the metabolome into a functional genomics approach to developing new drugs. It can be used in screening kinases and their metabolic targets, which can therefore be more efficiently characterized, speeding up and improving drug testing, approval and labeling processes by saving trial and error type study costs in drug testing.

Biomarkers, Tumor↗

PubMedDate not supplied

Genomics and the search for novel biomarkers in toxicology.

The advent of 'genomics' technology, in particular transcript profiling, has already had a measurable impact on the drug discovery process in the areas of target identification and validation. This review is concerned with the potential application of this technology to toxicology and drug safety assessment, with particular emphasis on biomarker discovery and characterization. An advantage (or possibly a drawback!) of transcript profiling is that candidate biomarkers of toxicity can be speedily identified, with the caveat that a significant amount of subsequent experimental and bioinformatic effort needs to be expended in order to evaluate and validate them. Attention is also drawn to the critical need for robust experimental design with studies of this type and to issues associated with the analysis of large data sets. In summary, while genomics technology undoubtedly offers much that can assist drug safety assessment, its potential has yet to be realized fully in this area. However, a large amount of resource continues to be applied to 'toxicogenomics'. Tangible benefits, in terms of new biomarkers of toxicity and reduced numbers of adverse drug effects, remain realistic objectives.

Animals↗

PubMed2002

Proteomics approaches to uncover the repertoire of circulating biomarkers for breast cancer.

There is substantial interest in applying proteomics to cancer biomarker discovery. Proteomics is particularly suited for profiling biological fluids and uncovering circulating markers and is currently being applied to the identification of novel biomarkers for breast cancer. Novel proteomic approaches include direct profiling of serum using mass spectrometry, application of a variety of strategies to harness immunity for cancer diagnosis, protein tagging to capture subproteomes rich in diagnostic markers, the use of protein microarrays, and the use of multi-dimensional liquid protein separation technologies for comprehensive profiling of serum and other biological fluids. It is likely that the application of a wide range of proteomics tools to breast cancer will yield a panel of markers that have utility for breast cancer diagnosis.

Autoantibodies↗

PubMed2000

Antioxidant biomarkers in freshwater bivalves, Unio tumidus, in response to different contamination profiles of aquatic sediments.

Antioxidant systems were studied in the freshwater bivalve Unio tumidus transplanted from a control site to four different contaminated areas, in order to study the biological response according to the contamination characteristics. Reduced and oxidized glutathione (GSH, GSSG), the activities of antioxidant enzymes such as selenium-dependent and non-selenium-dependent glutathione peroxidases (SeGPx and non-SeGPx), and glutathione reductase (GRd) were measured in the gills and the digestive gland of the mussels after 15 days of exposure at different sites. Lipid peroxidation (LPO) was evaluated by means of malondialdehyde measurements (MDA). The four sites investigated were located in the valleys of Fensch (F), Moselle (M), Lot et Garonne (LG), and Sarthe (S). At each site, the bivalves were placed upstream (Up) from an identified pollution source (a cokery, a laundry, or a foundry) and downstream (Do), close to the effluent outfall (Do(1)) or farther (Do(2)). The goal was to study the antioxidant response in relation to the pollution gradient. Metals and congeners of PAHs, PCBs, and organochlorinated pesticides were analyzed in the river sediments of each station. The exposure of the bivalves at the most highly polluted sites or close to the pollution source led to a sharp depletion in some antioxidant parameters, namely GRd, SeGPx, and GSH. The decrease in enzyme activities could reach 80% for GRd and 70% for SeGPx, while GSH depletion could yield 70%, leading then in an induction of lipid peroxidation, either in the digestive gland or in the gills. The higher the MDA concentrations, the lower the activity of these three antioxidant parameters, suggesting that they could be biomarkers for toxicity. Yet, a depletion in these parameters was sometimes insufficient for cytotoxicity to be induced, since lipid peroxidation failed to appear in some cases where antioxidant depletion was clear, although not so severe. The response of the gills and the digestive gland was not always paralleled, which can be explained by differences in the bioavailability of pollutants. In some cases, a relationship was not found between the antioxidant response and the degree and the type of contamination in sediments, suggesting that the effects could result from nonidentified pollutants or/and be indicators of bio-availability.

Animals↗

PubMed2005

Differential gene expression in human peripheral blood mononuclear cells induced by cigarette smoke and its constituents.

In current molecular epidemiology studies, a wide range of methods are used to monitor early biological effects after exposure to xenobiotic agents. Gene expression profiling is considered a promising tool that may provide more sensitive, mechanism-based biomarkers. As a first step toward obtaining information on the applicability of gene expression profiles as a biomarker for early biological effects of carcinogen exposure, we conducted in vitro studies on human peripheral blood mononuclear cells (PBMC). We used cigarette smoke condensate (CSC) and a selection of its genotoxic constituents as model agents, applying cDNA microarray technology to investigate modulated gene expression. In independent experiments using cells from several donors, quiescent PBMC were exposed for 18 h, followed by gene expression analyses on a microarray containing 600 toxicologically relevant genes. The search for candidate biomarker genes was binomial: first we looked for genes responding similarly to all agents; second, for agent-specific genes. Many genes were significantly deregulated by all compounds, but as the direction of deregulation frequently differed per agent, they are not useful as generic biomarkers. Cigarette smoke condensate modulated the expression of many more genes than any of its constituents, with the largest effect in SERPINB2. The affected genes are involved in immune or stress responses, but surprisingly no genes involved in DNA damage response were modulated, and only a few in DNA repair. In conclusion, several genes have been identified as potential biomarkers for population studies on early biological effects caused by cigarette smoke exposure, but no genes were identified that represent a generic biomarker.

Base Sequence↗

PubMed2006

Clinical proteomics: searching for better tumour markers with SELDI-TOF mass spectrometry.

Recently, the focus of cancer research has expanded from genetic information in the human genome to protein expression analyses. Because this 'proteome' reflects the state of a cell, tissue or organism more accurately, much is expected from proteomics to yield better tumour markers for disease diagnosis and therapy monitoring. Some current proteomic technologies are particularly suitable for protein profiling in the search for new biomarkers. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry has been used frequently, highlighting many new proteins as biomarkers (e.g. for ovarian, breast, prostate and colorectal cancer). However, it is becoming increasingly recognized that reproducibility and validation of these biomarkers should be addressed carefully, as should their origin and identity. If these efforts are made, protein profiling can contribute to the better diagnosis of patients and the optimization of their treatment.

Biomarkers, Tumor↗